TILs May Guide Treatment De-Escalation in ERBB2-Positive Breast Cancer

For patients with early ERBB2 (formerly HER2)–positive breast cancer, tumor-infiltrating lymphocytes (TILs) may play a crucial role in guiding treatment decisions.¹ A new follow-up analysis of the ShortHER randomized clinical trial (NCT00629278) found that higher TIL levels were associated with improved distant disease-free survival (DDFS) and overall survival (OS).

The findings suggest that patients with TILs at or above 20% can safely undergo shorter trastuzumab and chemotherapy regimens without increased risk of relapse or death, potentially leading the way for more personalized, less intensive treatment strategies.

A follow-up of the ShortHER trial suggests tumor-infiltrating lymphocytes (TILs) can help identify patients who may benefit from shorter trastuzumab and chemotherapy regimens. | Image credit: Valerii Apetroaiei - stock.adobe.com

The analysis is published in JAMA Oncology.

“This updated analysis from the ShortHER trial provides, to our knowledge, the first evidence of an independent effect of TILs on OS in patients with ERBB2-positive early breast cancer treated with adjuvant chemotherapy and trastuzumab,” the researchers of the study wrote.

ERBB2-positive breast cancer is a subtype of breast cancer characterized by the overexpression of the ERBB2 (formerly HER2) protein, a receptor that regulates cell growth and division.² In approximately 20% of breast cancers, the ERBB2 gene is amplified, leading to uncontrolled cancer cell growth.

ShortHER was a multicenter, phase 3 noninferiority study conducted in Italy to evaluate the duration of adjuvant trastuzumab in ERBB2-positive early breast cancer. A total of 1254 patients were randomized to receive either 9 weeks or 1 year of trastuzumab combined with chemotherapy, with different chemotherapy regimens assigned to each arm. DFS was the primary endpoint, with OS analyzed as a secondary outcome. TILs were centrally assessed using hematoxylin-eosin staining, and ERBB2 and hormone receptor status were evaluated locally.

Among 866 evaluable patients, TILs were associated with improved outcomes. Each 5% increase in TILs correlated with better DDFS (HR, 0.87; 95% CI, 0.80-0.95; P = .001) and OS (HR, 0.89; 95% CI, 0.81-0.98; P = .01). The 10-year OS rate progressively increased with higher TIL levels, reaching 98.1% for patients with TILs of 50% or greater.

Importantly, treatment benefit varied by TIL status. Patients with TILs below 20% had better outcomes with long compared with short trastuzumab treatment (10-year DDFS, 88.7% vs 81.0%), whereas those with TILs of 20% or higher showed superior outcomes with the shorter regimen (10-year DDFS, 92.2% vs 87.1%; P for interaction = .01). Similarly, OS trends favored short treatment in patients with higher TILs (93.1% vs 89.3%), whereas those with lower TILs had better survival with the long regimen (91.3% vs 86.9%; P for interaction = .06).

However, the researchers noted some limitations. Only 69% of the overall ShortHER population had evaluable TIL data, though this proportion aligns with similar studies.³ Additionally, the analysis was not pre-specified in the trial protocol, which may have introduced potential biases in the interpretation of results. Another key limitation was the arbitrary selection of the 20% TIL cut-off, making analyses that categorize TILs as a binary variable exploratory rather than definitive.

Despite these limitations, the researchers believe the findings highlight the prognostic and predictive role of TILs in tailoring breast cancer treatment duration.

“Validation is needed to confirm that patients with high TILs can safely undergo treatment de-escalation,” wrote the researchers.¹ “These findings support the integration of immune-related features into prognostic tools for ERBB2-positive early breast cancer, moving toward personalized treatment strategies beyond clinical-pathological features.”

References

1. Dieci MV, Bisagni G, Bartolini S, et al. Tumor-infiltrating lymphocytes and survival outcomes in early ERBB2-positive breast cancer: 10-year analysis of the ShortHER randomized clinical trial. JAMA Oncol. Published online February 13, 2025. doi:10.1001/jamaoncol.2024.6872

2. Idossa D, Borrero M, Blaes A. ERBB2-low (also known as HER2-low) breast cancer. JAMA Oncol. 2023;9(4):576. doi:10.1001/jamaoncol.2022.6889

3. Dieci MV, Conte P, Bisagi G, et al. Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer. Annals of Oncology, Volume 30, Issue 3, 418 - 423